The consequences of a viral infection depend upon a number of factors, both viral and host. These factors which affect pathogenesis include the number of infecting viral particles and their path to susceptible cells, the speed of viral multiplication and spread, the effect of the virus on cell functions, the host's secondary responses to the cellular injury, and the immunologic and non-specific defenses of the host. In general, the effects of viral infection include acute and chronic clinical diseases, asymptomatic infections, induction of various cancers, and chronic progressive neurological disorders. Viruses are potent infectious pathogenic agents because virions produced in one cell can invade other cells and thus cause a spreading infection. Viruses cause important functional alterations of the invaded cells, often resulting in cellular death.
Viral infections continue to be a major medical problem throughout the world. For example, acute and chronic hepatitis virus infection and its sequelae present a major problem. In fact, approximately 5% of the world's population, probably at least 400 million people in the world today, are infected with the hepatitis B virus (HBV). HBV presents a high risk of acute fulminant hepatitis as well as chronic liver disease, including cirrhosis, chronic active hepatitis, and the eventual development of primary hepatocellular carcinoma in individuals who remain chronic carriers of the virus.
The dramatic effects of the human immunodeficiency virus (HIV) provide another illustration of the results of viral disease. There are currently more than 27,700 diagnosed cases of AIDS in the United States, and the U.S. Public Health Service predicts that by the end of 1991 more than 179,000 persons will have the disease. Thus, intense medical research is being devoted to the development of diagnostic tools and vaccines to counter HIV. AIDS and hepatitis represent only two of the diseases wrought by viral infection.
Therapeutic studies during the last ten years have identified promising drugs with antiviral effects, including the nucleotide analog adenine arabinoside (Ara-A), its more soluble monophosphate Ara-AMP, and Interferon-alpha. Although effective in some patients, such agents have been shown frequently to result in only a transient response or to have significant toxicity. Accordingly, there is a continuing need for methods and therapeutic agents to stop viral replication and prevent the spread of the virus to additional cells. However, this goal presents considerable difficulties. A major problem is that of inhibiting the virus without harming the host cells. The dependence of viral multiplication on cellular genes limits the points of differential attack. Even the largest viruses have fewer biochemical reactions that are unique in relation to the cells of the host. Further, it is only after extensive viral multiplication and cellular alteration have occurred that viral infections become evident. Therefore, the most feasible approach to control viral infection is prophylaxis. Therapy in most cases is limited to situations where the killing of some uninfected cells can be tolerated if the damage is subsequently repaired.
Another important limitation of antiviral therapy is the emergence of resistant mutants. In order to avoid their selection, the principles valid for bacteria are equally applicable to viruses: adequate dosage, multi-drug treatment, and avoiding therapy unless clearly indicated. Therefore, because of the serious nature of viral infection and the obstacles presented by the nature of the infecting virus, there is an urgent need for methods which control viral replication. A method which would be applicable to RNA and DNA viruses would have widespread applicability.
Synthetic antisense oligonucleotides have been used as inhibitors of viral gene expression. Smith et al., Proc. Natl. Acad. Sci. USA, 2787-2791 (1986), report antiviral activity of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type I immediate early pre-mRNAs 4 and 5. See also: Agris et al., Inhibition of vesicular stomatitis virus protein synthesis and infection by methylphosphonates, Biochem. 25, 6268-6275 (1986); Zamecnik et al., Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide, Proc. Natl. Acad. Sci. USA 75:280-284 (1978); and Zamecnik et al., Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA, Proc. Natl. Acad. Sci. USA 83, 4143-4146 (1986). Goodarzi et al., J. Gen. Virol. 71:3021-3025 (1990), report inhibition of expression of the gene for hepatitis B virus surface antigen by antisense oligodeoxynucleotides directed at the cap site of mRNA and regions of the translational initiation site of the HBsAg gene.